DEFERASIROX Drug Interactions: What You Need to Know

INTERACTIONS Do not take deferasirox tablets for oral suspension with aluminum-containing antacid preparations. (7.1) Deferasirox tablets for oral suspension increases the exposure of the CYP2C8 substrate repaglinide. Consider repaglinide dose reduction and monitor blood glucose levels. (7.3) Avoid the use of deferasirox tablets for oral suspension with CYP1A2 substrate theophylline. (7.4) Deferasirox increases exposure of busulfan. Monitor plasma concentrations of busulfan when coadministered with deferasirox to allow dose adjustment of busulfan as needed. (7.7)

7.1 Aluminum-Containing Antacid Preparations The concomitant administration of deferasirox tablets for oral suspension and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, do not take deferasirox tablets for oral suspension with aluminum-containing antacid preparations due to the mechanism of action of deferasirox tablets for oral suspension.

7.2 Agents Metabolized by CYP3A4 Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> .

7.3 Agents Metabolized by CYP2C8 Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If deferasirox tablets for oral suspension and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely monitor patients for signs of exposure related toxicity when deferasirox tablets for oral suspension are coadministered with other CYP2C8 substrates <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.

7.4 Agents Metabolized by CYP1A2 Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An increase in theophylline plasma concentrations could lead to clinically significant theophylline-induced CNS or other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine) with deferasirox tablets for oral suspension. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with deferasirox tablets for oral suspension. Closely monitor patients for signs of exposure related toxicity when deferasirox tablets for oral suspension are coadministered with other drugs metabolized by CYP1A2 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> .

7.5 Agents Inducing UDP-glucuronosyltransferase (UGT)

Metabolism

Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of deferasirox tablets for oral suspension with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in deferasirox tablets for oral suspension efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of potent UGT inducers with deferasirox tablets for oral suspension. Consider increasing the initial dose of deferasirox tablets for oral suspension if you must coadminister these agents together [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)] .

7.6 Bile Acid Sequestrants Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with deferasirox tablets for oral suspension due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of deferasirox tablets for oral suspension <span class="opacity-50 text-xs">[see Dosage and Administration (2.5), Clinical Pharmacology (12.3)]</span> .

7.7 Busulfan Increased exposure of busulfan was observed with concomitant use with deferasirox. Monitor plasma concentrations of busulfan when coadministered with deferasirox to allow dose adjustment of busulfan as needed <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.

Deferasirox tablets for oral suspension are contraindicated in patients with:

• Estimated GFR less than 40 mL/min/1.73 m 2 [see Dosage and Administration ( Error! Hyperlink reference not valid. ), Warnings and Precautions ( Error! Hyperlink reference not valid. )];
• Poor performance status [see Warnings and Precautions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )];
• High-risk myelodysplastic syndromes (this patient population was not studied and is not expected to benefit from chelation therapy);
• Advanced malignancies [see Warnings and Precautions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )];
• Platelet counts less than 50 x 10 9 /L [see Warnings and Precautions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]; Known hypersensitivity to deferasirox or any component of deferasirox tablets for oral suspension [see Warnings and Precautions ( Error! Hyperlink reference not valid. ), Adverse Reactions ( Error! Hyperlink reference not valid. )] .
• Estimated GFR less than 40 mL/min/1.73 m 2 . ( 4 )
• Patients with poor performance status. ( 4 )
• Patients with high-risk myelodysplastic syndrome (MDS). ( 4 )
• Patients with advanced malignancies. ( 4 )
• Patients with platelet counts less than 50 x 10 9 /L. ( 4 )
• Known hypersensitivity to deferasirox or any component of deferasirox tablets for oral suspension. ( 4 )

AND PRECAUTIONS Acute Kidney Injury: Measure serum creatinine in duplicate before starting therapy. Monitor renal function during deferasirox tablets for oral suspension therapy and reduce dose or interrupt therapy for toxicity. (2.1, 2.4, 5.1)

Hepatic

Toxicity: Monitor hepatic function. Reduce dose or interrupt therapy for toxicity. (5.2) Fatal and Nonfatal Gastrointestinal Bleeding, Ulceration, and Irritation: Risk may be greater in patients who are taking deferasirox tablets for oral suspension in combination with drugs that have known ulcerogenic or hemorrhagic potential. (5.3)

Bone Marrow

Suppression: Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events; monitor blood counts during deferasirox tablets for oral suspension therapy. Interrupt therapy for toxicity. (5.4) Age-related Risk of Toxicity: Monitor elderly and pediatric patients closely for toxicity. (5.5)

Hypersensitivity

Reactions: Discontinue deferasirox tablets for oral suspension for severe reactions and institute medical intervention. (5.7)

Severe Skin

Reactions, including Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue deferasirox tablets for oral suspension. (5.8)

5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome Deferasirox tablets for oral suspension are contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2 . Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m 2 . If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6)]</span> . For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m 2 ) reduce the starting dose by 50% <span class="opacity-50 text-xs">[see Dosage and Administration (2.4, 2.5), Use in Specific Populations (8.6)]</span> . Deferasirox tablets for oral suspension can cause acute kidney injury including renal failure requiring dialysis that has resulted in fatal outcomes. Based on postmarketing experience, most fatalities have occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, adult and pediatric deferasirox tablets for oral suspension-treated patients with no preexisting renal disease experienced dose-dependent mild, non-progressive increases in serum creatinine and proteinuria. Preexisting renal disease and concomitant use of other nephrotoxic drugs may increase the risk of acute kidney injury in adult and pediatric patients. Acute illnesses associated with volume depletion and overchelation may increase the risk of acute kidney injury in pediatric patients. In pediatric patients, small decreases in eGFR can result in increases in deferasirox tablets for oral suspension exposure, particularly in younger patients with body surface area typical of patients less than age 7 years. This can lead to a cycle of worsening renal function and further increases in deferasirox tablets for oral suspension exposure, unless the dose is reduced or interrupted. Renal tubular toxicity, including acquired Fanconi syndrome, has been reported in patients treated with deferasirox tablets for oral suspension, most commonly in pediatric patients with beta-thalassemia and serum ferritin levels less than 1,500 mcg/L <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.4 ), Clinical Pharmacology (12.3) ]</span>. Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose. Use prediction equations validated for use in adult and pediatric patients to estimate GFR. Obtain serum electrolytes and urinalysis in all patients to evaluate renal tubular function <span class="opacity-50 text-xs">[see Dosage and Administration (2.1, 2.2)]</span>. Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated. Monitor serum ferritin monthly to evaluate for overchelation. Use the minimum dose to establish and maintain a low iron burden. Monitor renal function more frequently in patients with preexisting renal disease or decreased renal function. In pediatric patients, interrupt deferasirox tablets for oral suspension during acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor renal function more frequently. Promptly correct fluid deficits to prevent renal injury. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal <span class="opacity-50 text-xs">[see Dosage and Administration (2.5), Warnings and Precautions (5.6), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.4)]</span>.

5.2 Hepatic Toxicity and Failure Deferasirox tablets for oral suspension can cause hepatic injury, fatal in some patients.

In Study

1, 4 patients (1.3%) discontinued deferasirox tablets for oral suspension because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure [see Adverse Reactions (6.1)] . Acute liver injury and failure, including fatal outcomes, have occurred in pediatric deferasirox tablets for oral suspension-treated patients. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for overchelation during a volume depleting event. Interrupt deferasirox tablets for oral suspension therapy when acute liver injury or acute kidney injury is suspected and during volume depletion. Monitor liver and renal function more frequently in pediatric patients who are receiving deferasirox tablets for oral suspension in the 20 to 40 mg/kg/day range and when iron burden is approaching normal. Use the minimum effective dose to achieve and maintain a low iron burden [see Dosage and Administration (2.5), Warnings and Precautions (5.6), Adverse Reactions (6.1)]. Measure transaminases [aspartate transaminase (AST) and alanine transaminase (ALT)] and bilirubin in all patients before the initiation of treatment, and every 2 weeks during the first month and at least monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations. Avoid the use of deferasirox tablets for oral suspension in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.7)] . Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.

5.3 Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation GI hemorrhage, including deaths, has been reported in deferasirox tablets for oral suspension-treated patients, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving deferasirox tablets for oral suspension <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . Monitor for signs and symptoms of GI ulceration and hemorrhage during deferasirox tablets for oral suspension therapy and promptly initiate additional evaluation and treatment if a serious GI adverse reaction is suspected. The risk of GI hemorrhage may be increased when administering deferasirox tablets for oral suspension in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There have been reports of ulcers complicated with GI perforation (including fatal outcome) <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> .

5.4 Bone Marrow Suppression Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with deferasirox tablets for oral suspension. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with deferasirox tablets for oral suspension in patients who develop cytopenias until the cause of the cytopenia has been determined. Deferasirox tablets for oral suspension are contraindicated in patients with platelet counts below 50 x 10 9 /L.

5.5 Age-Related Risk of Toxicity Elderly Patients Deferasirox tablets for oral suspension have been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly in elderly patients. Monitor elderly patients treated with deferasirox tablets for oral suspension more frequently for toxicity <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5)]</span> .

Pediatric Patients

Deferasirox tablets for oral suspension has been associated with serious and fatal adverse reactions in pediatric patients in the postmarketing setting. These events were frequently associated with volume depletion or with continued deferasirox tablets for oral suspension doses in the 20 to 40 mg/kg/day range when body iron burden was approaching or in the normal range. Interrupt deferasirox tablets for oral suspension in patients with volume depletion, and resume deferasirox tablets for oral suspension when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox tablets for oral suspension in the 20 to 40 mg/kg/day range when iron burden is approaching the normal range. Use the minimum effective dose to achieve and maintain a low iron burden [see Dosage and Administration (2.4), Warnings and Precautions (5.6), Use in Specific Populations (8.4)].

5.6 Overchelation For patients with transfusional iron overload, measure serum ferritin monthly to assess the patient’s response to therapy and minimize the risk of overchelation. An analysis of pediatric patients treated with deferasirox tablets for oral suspension in pooled clinical trials (n=158) found a higher rate of renal adverse reactions among patients receiving doses greater than 25 mg/kg/day while their serum ferritin values were less than 1,000 mcg/L. Consider dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels during these periods. Use the minimum effective dose to maintain a low-iron burden <span class="opacity-50 text-xs">[see Adverse Reaction (6.1), Use in Specific Populations (8.4)]</span>. If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the dose is greater than 25 mg/kg/day <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . If the serum ferritin falls below 500 mcg/L, interrupt therapy with deferasirox tablets for oral suspension and continue monthly monitoring. Evaluate the need for ongoing chelation for patients whose conditions do not require regular blood transfusions. Use the minimum effective dose to maintain iron burden in the target range. Continued administration of deferasirox tablets for oral suspension in the 20 to 40 mg/kg/day range when the body iron burden is approaching or within the normal range has resulted in life-threatening adverse reactions <span class="opacity-50 text-xs">[see Dosage and Administration (2.1)]</span> . For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment. Interrupt deferasirox tablets for oral suspension administration when the LIC is less than 3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt deferasirox tablets for oral suspension and obtain a confirmatory LIC <span class="opacity-50 text-xs">[see Clinical Studies (14)]</span> .

5.7 Hypersensitivity Deferasirox tablets for oral suspension may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> . If reactions are severe, discontinue deferasirox tablets for oral suspension and institute appropriate medical intervention. Deferasirox tablets for oral suspension are contraindicated in patients with known hypersensitivity to deferasirox products and should not be reintroduced in patients who have experienced previous hypersensitivity reactions on deferasirox products due to the risk of anaphylactic shock.

5.8 Severe Skin Reactions Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal have been reported during deferasirox tablets for oral suspension therapy <span class="opacity-50 text-xs">[see Adverse Reactions (6.1, 6.2)]</span> . Cases of erythema multiforme have been observed. Advise patients of the signs and symptoms of severe skin reactions, and closely monitor. If any severe skin reactions are suspected, discontinue deferasirox tablets for oral suspension immediately and do not reintroduce deferasirox tablets for oral suspension therapy.

5.9 Skin Rash Rashes may occur during deferasirox tablets for oral suspension treatment <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . For rashes of mild to moderate severity, deferasirox tablets for oral suspension may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with deferasirox tablets for oral suspension. Reintroduction at a lower dose with escalation may be considered after resolution of the rash.

5.10 Auditory and Ocular Abnormalities Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of less than 1% with deferasirox tablets for oral suspension therapy in the clinical studies. The frequency of auditory adverse reactions was increased among pediatric patients who received deferasirox tablets for oral suspension doses greater than 25 mg/kg/day when serum ferritin was less than 1,000 mcg/L <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6)]</span>. Perform auditory and ophthalmic testing (including slit-lamp examinations and dilated fundoscopy) before starting deferasirox tablets for oral suspension treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.